The etiology of the human demyelinating disease, multiple sclerosis (MS), is not known. Current hypotheses propose that the disease is autoimmune, viral or both in nature. Thus far, no autoimmune animal model perfectly mimics the clinical and pathological features of patients with MS. Similarly, various immunological treatments which ameliorate a central nervous system (CNS) autoimmune disease model, experimental allergic encephalomyelitis (EAE) when conducted with MS patients, for the most part have not modulated the disease. Although, one treatment which lessens EAE does alter the course of MS, that being interferon beta. Thus, there is precedence for an autoimmune based model. However, there is equally convincing evidence that there is viral involvement in human CNS demyelinating disease. For example, the next most common naturally occurring demyelinating diseases besides MS involves virus infections. The post-viral encephalomyelopathies such as post measles virus encephalomyelopathy consists of infection with measles virus followed by; clinical symptoms of CNS involvement, the presence of increased numbers of myelin basic protein specific T cells and areas of demyelination. Most of these individuals recover, but approximately 10% of those involved have residual effects. In addition, virus infections have also been associated with either the initiation or exacerbations observed in MS. Thus, while the etiology of MS is unknown there is good evidence that viruses play a role in human demyelinating disease and possibly MS. Since experiments with MS subjects in most instances are not ethical, animal-virus infection models which mimic many of the features of MS, offer a rational approach. We have been using the Theiler's murine encephalomyelitis virus (TMEV) infection of SJL/J mice as a model for human demyelinating diseases. This is a naturally occurring infection of mice and the mouse is the natural host for the virus. The goals and aims of this proposal are to study the interactions of the virus and the host and how this leads to CNS demyelinating disease. The first aim is to determine the structural sites which are important for viral tropism and persistence in the context of pathogenesis. The second aim is to explore the immunologic contributions for protection from CNS disease and viral clearance. The third aim is to determine the cellular receptors on CNS and non-CNS cell-types which may be involved in viral tropism and disease.